scholarly journals Proinflammatory Effects of Ubiquitin-Specific Protease 5 (USP5) in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-Bo Luo ◽  
Jian-Cheng Xi ◽  
Zhen Liu ◽  
Yu Long ◽  
Li-tao Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Autoimmune Inflammatory Disease ◽  
Specific Protease ◽  
Inflammatory Processes ◽  
Ubiquitin Specific Protease ◽  
Signaling Activation ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a worldwide chronic autoimmune inflammatory disease which is affecting approximately 1% of the total population. It is characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS) and increased production of proinflammatory cytokines. In the current study, we were aiming to investigate the role of ubiquitin-specific protease 5 (USP5) in the inflammatory process in RA-FLS. Expression of USP5 was found upregulated in RA-FLS compared with that in osteoarthritis- (OA-) FLS, and IL-1β stimulation increased USP5 expression in a time-dependent manner. Furthermore, we found that USP5 overexpression significantly aggravated proinflammatory cytokine production and related nuclear factor κB (NF-κB) signaling activation. Consistently, silencing of USP5 decreased the release of cytokines and inhibited the activation of NF-κB. In addition, USP5 was found to interact with tumor necrosis factor receptor-associated factor 6 (TRAF6) and remove its K48-linked polyubiquitination chains therefore stabilizing TRAF6. Our data showed that a USP5-positive cell regulates inflammatory processes in RA-FLS and suggested USP5 as a potential target for RA treatment.

USP22 promotes pro-inflammatory responses in Pseudomonas aeruginosa-induced keratitis by targeting TRAF6

2020 ◽  
Author(s):  
DI CHEN ◽  
DAWEI SONG ◽  
YIBIN MA ◽  
WEIZHAO LU ◽  
JIANFENG QIU ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Vision Loss ◽  
Inflammatory Responses ◽  
Tumor Necrosis Factor Receptor ◽  
Raw264.7 Cells ◽  
Control Plasmid ◽  
Specific Protease ◽  
Inflammatory Processes ◽  
Ubiquitin Specific Protease ◽  
Necrosis Factor

Abstract Background Pseudomonas aeruginosa (PA)-induced keratitis is characterized by inflammatory epithelial edema, stromal infiltration, corneal ulceration, and can lead to vision loss. In the present study, we aim to study the effect of ubiquitin-specific protease 22 (USP22) on PA-induced keratitis. Methods Lentivirus containing control plasmid or shRNA targeting USP22 were used to silence the expression of USP22 in mouse corneas and cultured RAW264.7 cells, the inflammatory processes were detected. Results We found the expression level of USP22 was significantly increased in both mouse corneas and cultured RAW264.7 cells after PA stimulation. In addition, we observed that silencing of USP22 attenuate disease progression, downregulate NF-κB pathway and suppressed the expression of pro-inflammatory cytokines after PA stimulation. Most importantly, we found the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was decreased by silencing of USP22, and USP22 was found to remove K48-linked poly-ubiquitination chains from TRAF6 to stabilize TRAF6 expression after PA infection. Conclusion This data indicated USP22 as a positive regulator of pro-inflammatory responses in PA induced keratitis.

TLRs Play Crucial Roles in Regulating RA Synoviocyte

2020 ◽  
Vol 20 (8) ◽  
pp. 1156-1165 ◽  
Author(s):  
Xuling Luo ◽  
Juncheng Cui ◽  
Xin Long ◽  
Zhiwei Chen
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Inflammatory Disease ◽  
Chinese Herb ◽  
Bone Destruction ◽  
Inflammatory Factors ◽  
Exact Role ◽  
Autoimmune Inflammatory Disease ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease comparing the inflammation of synovium. Macrophage-like synoviocytes and fibroblast-like synoviocytes (synoviocytes) are crucial ingredients of synovium. Therein, a lot of research has focused on synoviocytes. Researches demonstrated that TLR1, TLR2, TLR3, TLR4, TLR5, TLR6 TLR7 and TLR9 are expressed in synoviocyte. Additionally, the expression of TLR2, TLR3, TLR4 and TLR5 is increased in RA synoviocyte. In this paper, we review the exact role of TLR2, TLR3, TLR4 and TLR5 participate in regulating the production of inflammatory factors in RA synoviocyte. Furthermore, we discuss the role of vasoactive intestinal peptide (VIP), MicroRNA, Monome of Chinese herb and other cells (Monocyte and T cell) influence the function of synoviocyte by regulating TLRs. The activation of toll-like receptors (TLRs) in synoviocyte leads to the aggravation of arthritis, comparing with angiogenesis and bone destruction. Above all, TLRs are promising targets for managing RA.

The Role of miR-382-5p in Rheumatoid Arthritis: An In Vitro Study with Fibroblast-Like Synoviocytes

2020 ◽  
Vol 10 (2) ◽  
pp. 169-175
Author(s):  
Deqian Meng ◽  
Wenyou Pan ◽  
Ju Li
Keyword(s):  
Rheumatoid Arthritis ◽  
In Vitro Study ◽  
Underlying Mechanism ◽  
High Morbidity ◽  
Systemic Autoimmunity ◽  
Autoimmune Inflammatory Disease ◽  
Proliferation And Invasion ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease with high morbidity. MiR-382-5p may be associated with progression from systemic autoimmunity to RA inflammation. The present study aims to investigate the underlying mechanism of miR-382-5p in the pathogenesis of RA. In present study, the decreased expression of miR-382-5p was observed in RA-FLSs. Furthermore, miR-382-5p overexpression inhibited the proliferation and invasion of RA-FLS cells. In addition, miR-382-5p overexpression inhibited the release of inflammatory cytokines and promoted apoptosis of RA-FLS cells. Finally, miR-382-5p overexpression induced inactivation of TLR4/NF-κB/Cox2 signaling pathway. Our findings implied that miR-382-5p exerts regulative effect on pathogenesis of RA and indicated that miR-382-5p may represent as an effective therapeutic target in the clinical treatment of RA.

Treatment with Melittin Induces Apoptosis and Autophagy of Fibroblast-like Synoviocytes in Patients with Rheumatoid Arthritis

2020 ◽  
Vol 21 (8) ◽  
pp. 734-740 ◽  
Author(s):  
Shou-di He ◽  
Ning Tan ◽  
Chen-xia Sun ◽  
Kang-han Liao ◽  
Hui-jun Zhu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Caspase 3 ◽  
Joint Destruction ◽  
Joint Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Caspase 9 ◽  
Inflammatory Processes ◽  
Related Proteins ◽  
Local Stimulation ◽  
Fibroblast Like Synoviocytes

Background: Melittin, the major medicinal component of honeybee venom, exerts antiinflammatory, analgesic, and anti-arthritic effects in patients with Rheumatoid Arthritis (RA). RA is an inflammatory autoimmune joint disease that leads to irreversible joint destruction and functional loss. Fibroblast-Like Synoviocytes (FLS) are dominant, special mesenchymal cells characterized by the structure of the synovial intima, playing a crucial role in both the initiation and progression of RA. Objective: In this study, we evaluated the effects of melittin on the viability and apoptosis of FLS isolated from patients with RA. Methods: Cell viability was determined using CCK-8 assays; apoptosis was evaluated by flow cytometry, and the expression levels of apoptosis-related proteins (caspase-3, caspase-9, BAX, and Bcl-2) were also determined. To explore whether melittin alters inflammatory processes in RA-FLS, IL-1β levels were determined using an enzyme-linked immunosorbent assay (ELISA). Furthermore, we performed GFP-LC3 punctate fluorescence dot assays and western blotting (for LC3, ATG5, p62, and Beclin 1) to assess autophagy in RA-FLS. Results: Our results show that melittin can significantly impair viability, promote apoptosis and autophagy, and inhibit IL-1β secretion in RA-FLS. Conclusion: Melittin may be useful in preventing damage to the joints during accidental local stimulation.

scholarly journals Role of MDA5 in regulating CXCL10 expression induced by TLR3 signaling in human rheumatoid fibroblast-like synoviocytes

2021 ◽  
Author(s):  
Tatsuro Saruga ◽  
Tadaatsu Imaizumi ◽  
Shogo Kawaguchi ◽  
Kazuhiko Seya ◽  
Tomoh Matsumiya ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Neutralizing Antibody ◽  
Poly I:C ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Inflammatory Reactions ◽  
Polyinosinic:Polycytidylic Acid ◽  
Tlr3 Signaling ◽  
Fibroblast Like Synoviocytes

AbstractC-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.

scholarly journals Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Zhang ◽  
Guoyu Yin ◽  
Heping Zhao ◽  
Hanzhi Ling ◽  
Zhen Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hyaluronic Acid ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Intracellular Degradation ◽  
Main Pathway ◽  
First Time

AbstractIn inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

scholarly journals Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Zhengru Liu ◽  
Mingming Qi ◽  
Shan Tian ◽  
Qian Yang ◽  
Jian Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Tight Junctions ◽  
Multiple Organ ◽  
Organ Injury ◽  
Pancreatic Acinar Cells ◽  
Stat3 Pathway ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Multiple Organ Injury

Ubiquitin-specific protease 25 (USP25) plays an important role in inflammation and immunity. However, the role of USP25 in acute pancreatitis (AP) is still unclear. To evaluate the role of USP25 in AP, we conducted research on clinical AP patients, USP25wild-type(WT)/USP25 knockout (USP25−/−) mice, and pancreatic acinar cells. Our results showed that serum USP25 concentration was higher in AP patients than in healthy controls and was positively correlated with disease severity. AP patients’ serum USP25 levels after treatment were significantly lower than that at the onset of AP. Moreover, USP25 expression was upregulated in cerulein-induced AP in mice, while USP25 deficiency attenuates AP and AP-related multiple organ injury. In vivo and in vitro studies showed that USP25 exacerbates AP by promoting the release of pro-inflammatory factors and destroying tight junctions of the pancreas. We showed that USP25 aggravates AP and AP-related multiple organ injury by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Targeting the action of USP25 may present a potential therapeutic option for treating AP.

scholarly journals Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

2019 ◽  
Vol 110 (1-2) ◽  
pp. 119-129 ◽  
Author(s):  
Antonella Sesta ◽  
Maria Francesca Cassarino ◽  
Mariarosa Terreni ◽  
Alberto G. Ambrogio ◽  
Laura Libera ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Pituitary Adenomas ◽  
Expression Profiles ◽  
Primary Cultures ◽  
Acth Secretion ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease ◽  
Acth Secreting

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

scholarly journals The targetable role of herpes virus-associated ubiquitin-specific protease (HAUSP) in p190 BCR-ABL leukemia

2016 ◽  
Vol 12 (5) ◽  
pp. 3123-3126 ◽  
Author(s):  
Giovanna Carrà ◽  
Cristina Panuzzo ◽  
Sabrina Crivellaro ◽  
Deborah Morena ◽  
Riccardo Taulli ◽  
...  
Keyword(s):  
Herpes Virus ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Herpès Virus
Sign in / Sign up

Export Citation Format

Share Document